Akt protects the heart against ischaemia-reperfusion injury by modulating mitochondrial morphology

2015 ◽  
Vol 113 (03) ◽  
pp. 513-521 ◽  
Author(s):  
Sang-Bing Ong ◽  
Andrew Hall ◽  
Rachel Dongworth ◽  
Siavash Kalkhoran ◽  
Aswin Pyakurel ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Cardiac Cells ◽  
Mitochondrial Morphology ◽  
Myocardial Infarct Size ◽  
Ischaemia Reperfusion Injury ◽  
Acute Ischaemia ◽  
Mptp Opening ◽  
Ischaemia Reperfusion ◽  
Mitochondrial Elongation

SummaryThe mechanism through which the protein kinase Akt (also called PKB), protects the heart against acute ischaemia-reperfusion injury (IRI) is not clear. Here, we investigate whether Akt mediates its cardioprotective effect by modulating mitochondrial morphology. Transfection of HL-1 cardiac cells with constitutively active Akt (caAkt) changed mitochondrial morphology as evidenced by an increase in the proportion of cells displaying predominantly elongated mitochondria (73 ± 5.0 % caAkt vs 49 ± 5.8 % control: N=80 cells/group; p< 0.05). This effect was associated with delayed time taken to induce mitochondrial permeability transition pore (MPTP) opening (by 2.4 ± 0.5 fold; N=80 cells/group: p< 0.05); and reduced cell death following simulated IRI (32.8 ± 1.2 % caAkt vs 63.8 ± 5.6 % control: N=320 cells/group: p< 0.05). Similar effects on mitochondrial morphology, MPTP opening, and cell survival post-IRI, were demonstrated with pharmacological activation of Akt using the known cardioprotective cytokine, erythropoietin (EPO). The effect of Akt on inducing mitochondrial elongation was found to be dependent on the mitochondrial fusion protein, Mitofusin-1 (Mfn1), as ablation of Mfn1 in mouse embryonic fibroblasts (MEFs) abrogated Akt-mediated mitochondrial elongation. Finally, in vivo pre-treatment with EPO reduced myocardial infarct size (as a % of the area at risk) in adult mice subjected to IRI (26.2 ± 2.6 % with EPO vs 46.1 ± 6.5 % in control; N=7/group: p< 0.05), and reduced the proportion of cells displaying myofibrillar disarray and mitochondrial fragmentation observed by electron microscopy in adult murine hearts subjected to ischaemia from 5.8 ± 1.0 % to 2.2 ± 1.0 % (N=5 hearts/group; p< 0.05). In conclusion, we found that either genetic or pharmacological activation of Akt protected the heart against acute ischaemia-reperfusion injury by modulating mitochondrial morphology.

scholarly journals Effects of Cardiovascular Risk Factors on Cardiac STAT3

2018 ◽  
Vol 19 (11) ◽  
pp. 3572 ◽  
Author(s):  
Márton Pipicz ◽  
Virág Demján ◽  
Márta Sárközy ◽  
Tamás Csont
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Reperfusion Injury ◽  
Cardiovascular Risk Factors ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition ◽  
Cardiac Cells ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Age Related

Nuclear, mitochondrial and cytoplasmic signal transducer and activator of transcription 3 (STAT3) regulates many cellular processes, e.g., the transcription or opening of mitochondrial permeability transition pore, and its activity depends on the phosphorylation of Tyr705 and/or Ser727 sites. In the heterogeneous network of cardiac cells, STAT3 promotes cardiac muscle differentiation, vascular element formation and extracellular matrix homeostasis. Overwhelming evidence suggests that STAT3 is beneficial for the heart, plays a role in the prevention of age-related and postpartum heart failure, protects the heart against cardiotoxic doxorubicin or ischaemia/reperfusion injury, and is involved in many cardioprotective strategies (e.g., ischaemic preconditioning, perconditioning, postconditioning, remote or pharmacological conditioning). Ischaemic heart disease is still the leading cause of death worldwide, and many cardiovascular risk factors contribute to the development of the disease. This review focuses on the effects of various cardiovascular risk factors (diabetes, aging, obesity, smoking, alcohol, depression, gender, comedications) on cardiac STAT3 under non-ischaemic baseline conditions, and in settings of ischaemia/reperfusion injury with or without cardioprotective strategies.

scholarly journals Effects of mycophenolate mofetil on acute ischaemia-reperfusion injury in rats and its consequences in the long term

2009 ◽  
Vol 25 (5) ◽  
pp. 1443-1450 ◽  
Author(s):  
M. Sabbatini ◽  
F. Uccello ◽  
V. Serio ◽  
G. Troncone ◽  
V. Varone ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Acute Ischaemia ◽  
Ischaemia Reperfusion

An Introduction to Cardioprotection

2011 ◽  
Keyword(s):  
Reperfusion Injury ◽  
Myocardial Injury ◽  
Artery Bypass ◽  
Bypass Graft ◽  
Myocardial Damage ◽  
Myocardial Salvage ◽  
Ischaemia Reperfusion Injury ◽  
Acute Ischaemia ◽  
Ischaemia Reperfusion ◽  
Considerable Morbidity

• In its broadest sense, the term ‘cardioprotection’ encompasses ‘all mechanisms and means that contribute to the preservation of the heart by reducing or even preventing myocardial damage’• However, for the purposes of this book, the term ‘cardioprotection’ will refer to the endogenous mechanisms and therapeutic strategies that reduce or prevent myocardial damage induced by acute ischaemia-reperfusion injury• In this context, cardioprotection begins with the primary prevention of coronary heart disease and includes the reduction of myocardial injury sustained during coronary artery bypass graft surgery, and an acute myocardial infarction, conditions with considerable morbidity and mortality• An understanding of the pathophysiology of acute myocardial ischaemia-reperfusion injury is essential when designing new cardioprotective strategies• Several methods exist for both quantifying myocardial damage induced by acute ischaemia-reperfusion injury and for assessing myocardial salvage following the application of cardioprotective strategies• Importantly, novel cardioprotective strategies must be capable of preventing and reducing myocardial damage over and above that provided by current optimal therapy.

Mitochondrial protein kinase Cϵ (PKCϵ): emerging role in cardiac protection from ischaemic damage

2007 ◽  
Vol 35 (5) ◽  
pp. 1052-1054 ◽  
Author(s):  
G.R. Budas ◽  
D. Mochly-Rosen
Keyword(s):  
Protein Kinase ◽  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Apoptotic Cell ◽  
Critical Role ◽  
Mitochondrial Protein ◽  
Permeability Transition ◽  
K Channel ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion

Mitochondria mediate diverse cellular functions including energy generation and ROS (reactive oxygen species) production and contribute to signal transduction. Mitochondria are also key regulators of cell viability and play a central role in necrotic and apoptotic cell death pathways induced by cardiac ischaemia/reperfusion injury. PKC (protein kinase C) ϵ plays a critical role in cardioprotective signalling pathways that protect the heart from ischaemia/reperfusion. Emerging evidence suggests that the cardioprotective target of PKCϵ resides at the mitochondria. Proposed mitochondrial targets of PKCϵ include mitoKATP (mitochondrial ATP-sensitive K+ channel), components of the MPTP (mitochondrial permeability transition pore) and components of the electron transport chain. This review highlights mitochondrial targets of PKCϵ and their possible role in cardioprotective signalling in the setting of ischaemia/reperfusion injury.

scholarly journals e0141 The effects and mechanisms between DIDS and EDRV on acute ischaemia-reperfusion injury myocardium

Heart ◽  
2010 ◽  
Vol 96 (Suppl 3) ◽  
pp. A45-A45
Author(s):  
L. Yan-xia ◽  
L. Jia-ni ◽  
S. Ming-zhi ◽  
Z. Meng ◽  
Z. Ya-li ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Ischaemia Reperfusion Injury ◽  
Acute Ischaemia ◽  
Ischaemia Reperfusion

scholarly journals Cysteine 202 of cyclophilin D is a site of multiple post-translational modifications and plays a role in cardioprotection

2020 ◽  
Author(s):  
Georgios Amanakis ◽  
Junhui Sun ◽  
Maria M Fergusson ◽  
Shane McGinty ◽  
Chengyu Liu ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
Mitochondrial Permeability Transition ◽  
Cysteine Residue ◽  
Cardiac Mitochondria ◽  
Cyclophilin D ◽  
Ischaemia Reperfusion Injury ◽  
Retention Capacity ◽  
Post Translational Modifications ◽  
Ischaemia Reperfusion ◽  
Ptp Opening

Abstract Aims Cyclophilin-D is a well-known regulator of the mitochondrial permeability transition pore (PTP), the main effector of cardiac ischaemia/reperfusion injury. However, the binding of CypD to the PTP is poorly understood. Cysteine 202 (C202) of CypD is highly conserved among species and can undergo redox-sensitive post-translational modifications. We investigated whether C202 regulates the opening of PTP. Methods and results We developed a knock-in mouse model using CRISPR where CypD-C202 was mutated to a serine (C202S). Infarct size is reduced in CypD-C202S Langendorff perfused hearts compared to wild type (WT). Cardiac mitochondria from CypD-C202S mice also have higher calcium retention capacity compared to WT. Therefore, we hypothesized that oxidation of C202 might target CypD to the PTP. Indeed, isolated cardiac mitochondria subjected to oxidative stress exhibit less binding of CypD-C202S to the proposed PTP component F1F0-ATP-synthase. We previously found C202 to be S-nitrosylated in ischaemic preconditioning. Cysteine residues can also undergo S-acylation, and C202 matched an S-acylation motif. S-acylation of CypD-C202 was assessed using a resin-assisted capture (Acyl-RAC). WT hearts are abundantly S-acylated on CypD C202 under baseline conditions indicating that S-acylation on C202 per se does not lead to PTP opening. CypD C202S knock-in hearts are protected from ischaemia/reperfusion injury suggesting further that lack of CypD S-acylation at C202 is not detrimental (when C is mutated to S) and does not induce PTP opening. However, we find that ischaemia leads to de-acylation of C202 and that calcium overload in isolated mitochondria promotes de-acylation of CypD. Furthermore, a high bolus of calcium in WT cardiac mitochondria displaces CypD from its physiological binding partners and possibly renders it available for interaction with the PTP. Conclusions Taken together the data suggest that with ischaemia CypD is de-acylated at C202 allowing the free cysteine residue to undergo oxidation during the first minutes of reperfusion which in turn targets it to the PTP.

Sign in / Sign up

Export Citation Format

Share Document